3-acyloxymethyl cephalosporins and method of preparation

ABSTRACT

3-CYCLOALKYLCARBONYLOXYMETHYL AND 3-CYCLOALYLALKANOYLOXYMETHYL $3-CEPHALOSPORINS (E.G., 7-(2&#39;&#39;-THIENYLACETAMIDO)-3-CYCLOBUTYLCARBONYLOXYMETHYL-$3-CEPHEM4-CARBOXYLIC ACID), ARE PREPARED BY REACTION OFA 7-ACYLAMIDO-$2-DESACETYLCEPHALOSPORIN WITH THE ANHYDRIDE OF AN ALIPHATIC CARBOXYLIC ACID TO FORM THE CORRESPONDING $2-ACYLOXYMETHYL CEPHALOSPORIN WHICH CAN BE OXIDIZED AND REDUCED TO FORM THE CORRESPONDING $3-COMPOUND.

United States Patent 3,728,342 3-ACYLOXYMETHYL CEPHALOSPORINS AND METHODOF PREPARATION Stjepan Kukolja, Indianapolis, Ind., assignor to EliLilly and Company, Indianapolis, Ind. N0 Drawing. Filed Dec. 3, 1970,Ser. No. 94,988

' Int. Cl. C07d 99/24 U.S. Cl. 260-243 c 9 Claims ABSTRACT OF THEDISCLOSURE This invention relates to certain3-cycloalkylcarbonyloxymethyl and 3-cycloalkylalkanoyloxymethyl A-cephalosporins, and to a new and improved process for their preparationfrom desacetylcephalosporins.

The semi-synthetic production of 7-acylamidodesacetoxycephalosporinantibiotics from penicillin starting materials has become of importancerecently, due to the process invention of Morin and Jackson (U.S. Pat.3,275,626) who describe and claim a process for converting penicillinsulfoxide esters to desacetoxycephalosporanic acid esters and to theimprovements on that Morin- Jackson process by Chauvette and Flynn (U.S.application Ser. No. 574,311, filed Aug. 23, 1966) who found thatcertain esters of the penicillin starting materials of the resultingdesacetoxycephalosporin ester products were more useful in the processin that they were more easily cleaved than those employed by Morin andJackson. Fur ther improvements of the Morin-Jackson process were claimedby Robin D. G. Cooper (U.S. applications Ser. No. 636,629, Ser. No.636,593, and Ser. No. 636,592, all filed May 8, 1967) who found that theuse of certain solvents directed the heat rearrangement of thepenicillin sulfoxide esters more specifically toward production of thecorresponding desacetoxycephalosporin esters and permitted the use oflower temperatures.

Some of the 7-acylamido desacetoxycephalosporanic acid compounds havebeen found to have unique properties as antibiotics in their own right.For example, cephalexin, 7-[D-2'-phenyl 2' aminoacetamido]desacetoxycephalosporanic acid zitterion and pharmaceutically acceptableanionic and cationic salt forms thereof are useful as oral antibioticsin combatting infections caused, for example, by penicillin resistantstrains of Staphylococcus aureus, and many other Gram-positive andGram-negative micro-organisms.

The products produced by the penicillin ring expansion process of Morinand Jackson, and/or the Chauvette- Flynn and Cooper improvements asdescribed above are A -desacetoxycephalosporins of the formula llR-0-Nrr-| l 2 0=8N 4 0 CH3 It isknown t hat compounds of the above typehave 3,728,342 Patented Apr. 17, 1973 effective antibiotic orantibacterial properties when the methyl group in the 3-position issubstituted by an alkanoyloxy group. For example, Flynn describes andclaims, in U.S. Pat. No. 3,218,318, the compound:

O (IJO'OH (II) known generically as cephalothin, a widely accepted andcommercially available antibiotic.

Flynn, in the aforementioned patent, described the preparation ofcephalothin by acylation of 7-aminocephalosporanic acid (7-ACA) doon(III) with Z-thienylacetyl chloride. As is known to those skilled in theart, 7-ACA is derived from. cephalosporin C C 430 OH (IV) which in turnis prepared by fermentation in accordance with known methods asdescribed by U.S. Pat. No. 3,093,638.

At the present time, limited methods are available to the prior art forthe preparation of compounds having an acyloxymethyl group in the3-position other than the naturally occurring acetoxy group.

In addition, in the preparation of the cephalosporin C by fermentation,the fermentation product includes desacetylcephalosporin C.

certain new antibiotically active cephalosporin compounds of the formulaCOOH wherein R is a heterocyclic group, n is zero or an integer from 1to 5 and R is C to C alkylene (i.e., methylene,

3 dimethylene, trimethylene). Representative of such cycloalkyl groupsinclude cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl,cyclopentylmethyl, cyclobutylpropyl, cyclohexyl, cyclohexylmethyl,cyclohexylethyl, cycloheptyl, cyclopropyl, etc.

It has been found that compounds of the foregoing type have a wide rangeof antibiotic or antibacterial activity against, for example,Gram-positive and Gram-negative micro-organisms.

Representative of preferred R groups include dioxanyl, Z-furyl, 3-fury1,imidazolyl, isoxazolyl, morpholinyl, oxazolyl, pyranyl, pyrazinyl,pyrazolyl, N-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidyl, N-pyrryl,2-pyrryl, 3-pyrryl, thiazolyl, Z-thienyl, 3-thienyl, 2-benzothienyl,3-benzothienyl, triazinyl, triazolyl and the like; the partially andcompletely hydrogenated derivatives of the foregoing, such astetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl,tetrahydropyrimidyl, pyrrolidyl and the like; as well as all of theforegoing groups which are substituted by one or more substituentsincluding, for example, C to C alkyl (e.g., methyl, ethyl, propyl,i'sopropyl), C to C alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), acyano group, a nitro group, a hydroxy group, halogen (e.g., chlorine,fluorine, bromine and iodine), a trifluoromethyl group, a carboxy group,an amino group, a C to C carboxyalkyl group (e.g., carboxymethyl,carboxypropyl, carboxyethyl, etc.) or a C to C carboxamidoalkyl group [HN-C(O)-a1kyl] (e.g., carboxamidornethyl, carboxamidoethyl, etc.), asrepresented by the picolyls, methylfuryls, methyl thienyls, nitrofuryl,cyanofuryl, nitrobenzothienyl, nitropyridyl, cyanopyridyl,methoxypyrimidyl, bromopyridyl, trifluoromethylpyridyl as Well as othersof the type described in Flynn US. Pat. No. 3,218,318.

For convenience, compounds of the present invention are named by the useof the cephem nomenclature system. Penarn nomenclature for thepenicillins is described by Sheehan, Henery-Logan, and Johnson in theJournal of the American Chemical Society (JACS), 75, 3292, footnote 2(1953), and has been adapted to the cephalosporins by Morin, Jackson,Flynn and Roeske [JACS, 84, 3400 (1962)]. In accordance with thesesysterms of. nomenclature penam and cepham refer respectively to thefollowing saturated ring systems:

Cephem refers to the cepham ring construction containing a double bond,the position of which is indicated by a prefixed A with a superscriptdenoting the lowest numbered carbon atom to which the double bond isconnected, or by the word delta with the same number relationship. Thus,for example, penicillin V, 6-phenoxymethylpenicillin, can be named6-(phenoxyacetamido)- 2,2-dimethyl-penam-3-carboxylic acid, and7-phenoxyacetamido desacetoxycephalosporanic acid can be named as7-phenoxyacetamido-3-methyl-A -cephem-4-carboxylic acid. Sometimes theposition of the double bond is indicated merely by the integer beforethe word cephem.

One of the most preferred compounds of the present invention can benamed 7-(2-thienylacetamido)-3-cyclobutylcar bonyloxymethyl-A-cephem-4-carboxylic acid.

Illustrative of the preferred compounds of this invention include thefollowing:

7- 2'-pyranylacetarnido -3-cyclobuty1carbonyloxyrnethyl- A-cephem-4-carboxy1ic acid 7- 3 '-pyranylacetami do 3-cyclohexylacetoxymethyl- A -cephem-4-carboxylic acid 7-2'-piperidylacetamido) -3-cyclohexylcarb onyloxymethyl-A-cephem-4-carboxylic acid 7- (2-piperidylacetamido)-3-cyclobutylcarbonyloxymethyl-A -cephern-4-carboxylic acid 72-pyridylacetamido -3 -cyclobutylcarbonyloxymethyl- A-cephern-4-carboxylic acid sodium salt 7 2-pyridylacetamido -3-cyclohexylacetoxymethyl- A -cephem-4-carboxylic acid 7- 5'-oxazolylacetamido) -3 -cyclopentylacetoxymethyl- A-cephem-4-carboxylic acid7-(5'-oxazo1y1acetamido)-3-cyclopentylpropionoxymethyl-A-cephem-4-carboxylic acid7-(4(5)imidazolylacetamido)-3-cyclobutylcarbonyloxymethyl-A-cephern-4-carboxylic acid 7 7- 2'-morpholinylacetamido -3-cycl0butylacetoxymethyl- A -cephem-4-carboxylic acid 7(2'-m0rph0linylacetamido) -3-cyclobutylacetoxymethy1-A-cephem-4-carboxylic acid sodium salt 7- (2-pyrazeny1acetamido-3-cyclohexylcarbonyl0xymethyl-A -cephem-4-carboxylic acid 7-( 5-imidoazolinylacetamido -3-cyclohexylpropionoxymethyl-A-cephem-4-carboxylic acid 7- 5 '-imidoazolinylacetamido) -3-cyclohexylacetoxymethyl-A -cephem-4-carboxylic acid 7-(2'-thienylacetamido) -3 -cyclobutylacetoxymethyl-A cephem-4-carboxylicacid potassium salt7-(3-brorno-2'-pyridylacetamido)-3-cyclohexylcarbonyloxyrnethyl-M-cephem-4-carboxylicacid 7-( 3 '-bromo-2'-pyridylacetamido -3-cyclobutylcarbonyloxymethyl-A-cephem-4-carboxylic acid 7- 5 '-fluor0-2-pyridylpropionacetamido-3-cyclopentylpropionoxymethy1-A -cephem-4-carboxylic acid 7- 5-pyrimidylpropionacetamido -3 -cyclobutylcarbonyl0xymethyl-A-cephem-4-carboxylic acid potassium salt 7 5'-pyrimidylpropionacetamido) -3-cyclopentaneacetoxymethyl-A-cephem-4-carboxylic acid7-(5-nitro-2'-thienylacetamido)3-cyclopentylpropionoxymethyl-A-cephem-4-carboxylic acid7-(5-nitro-2'-thienylacetamido)-3-cyclopentanoyloxymethyl-Acephem-4-carboxylic acid potassium salt 7-(2'-furylbutyrylacetamido-3-cyclobutylcarbonyloxymethyl-A cephem-4-carboxylic acid 7(2-thiazolylacetamido -3 -cyc1ohexylcarb onyloxymethyl-A-cephem-4-carboxylic acid 7 2-thienylvaleramido) -3 -cyclopentylpropionoxymethyl-A -cephem-4-carboxylic acid 7- 3-thienylhexanoylamido) -3 -cyclopentylcarbonyloxymethy1-A-cephem-4-carboxylic acid 7 a-picolyl-3 '-acetamido)-3-cyclobutylcarbonyloxymethyl-A -cephem-4-carboxylic acid 7-(2-thienylpropionamido -3 -cyclopropylcarb onyloxymethyl-A-cephem-4-carboxylic acid 7 (2-thienylpropionamido) -3 -cyclopropylcarbonyloxymethyl-A -cephern-4-carboxylic acid 7 7- 2'-rnethyl-3'-furylacetamido -3 -cyclobutylpropionoxymethyl-A -cephem-4-carboxylicacid 7- (2'-furyln-butylamido) -3 -cyclopentylpropionoxymethyl-A-cephem-4-carboxylic acid 7- (2-furyl-nbutylamido -3-cyclohexylacetoxymethyl- A -cephem-4-carboxy1ic acid 7-2'-triazinylacetamido -3-cyclopentaneacetoxymethyl- A-cephem-4-carboxylic acid7-(5-methoxy-3-pyridylacetamido)-3-cyclohexylacetoxymethyl-A-cephern-4-carboxylic acid7-(5-methoxy-3-pyridylacetamido)-3-cyclopropylcarbonyloxymethyl-A-cephem-4-carboxylic acid7-(2'-triazinylacetamido)-3-cyclohexylpropionoxymethyl-A-cephem-4-carboxylic acid.

As is the case with the penicillins to which the compounds of thisinvention are related in some degree, numerous salts, esters, amides andlike derivatives thereof can be prepared by combination withnon-toxicpharmaceutically acceptable cations, alcohols, ammonia, and amines. Suchderivatives can be regarded as equivalent to the compounds disclosed,and are included within the scope of the present invention.

For purposes of illustration, there can be mentione several types ofcationic salts which can be prepared from compounds of Formula VIincluding for example, water-soluble salts such as the sodium,potassium, lithium, ammonium and substituted ammonium salts, as well asthe less water-soluble salts such as the calcium, barium, procaine,quinine and dibenzylethylenediamine salts.

Another concept of the invention resides in a new and improved processwhich represents a heretofore unavailable, key chemical procedure makingit possible to prepare the novel compounds described above. It has beenfound in accordance with the practice of the process of this inventionthat a 7-acylamido-3-acyloxymethyl-A cephalosporin having the formula HRr-ii-NH O 0L: ii-oHr-o-b-R;

boon, (X

wherein R, is the residue of the acylamido group in the 7-position, R ishydrogen or the residue of an ester forming alcohol and R is a C to C7alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,etc.) or a cycloalkyl group {Don- CH2)...

CH (XII) o Brii-NH 0* N -cmon C JOORI (XIII) wherein R, and R are asdefined above.

As the acid anhydride, use can be made of any of the aliphaticcarboxylic acid anhydrides containing 4--20 carbon atoms. Preferredanhydrides are those having the general formula V '0 O R5-H3O( 1-R5(XIV) wherein R is an alkyl group containing 1-7 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl,heptyl, etc., or a cycloalkyl having the formula flH-l CHzhr- 2 CH (xv)wherein R is C to C alkylene (i.e., methylene, dimethylene,trimethylene) and m is zero or an integer from 1 to 4. Representative ofthe foregoing cycloalkyl groups include cyclobutyl, cyclobutylmethyl,cyclobutylethyl, cyclo- 6 pentyl, cyclopentylethyl, cyclopentylmethyl,cyclohexyl, cyclohexylmethyl, cyclopropyl, cyclopropylmethyl, etc.

Illustrative of the carboxylic acid anhydrides which can be employed inaccordance with the practice of the process of this invention includeacetic anhydride, propionic anhydride, butyric anhydride, isobutyricanhydride, pentanoic anhydride, hexanoic anhydride, heptanoic anhydride,cyclobutane carboxylic anhydride, cyclopentane carboxylic anhydride,cyclohexane carboxylic anhydride, cyclobutaneacetic anhydride,cyclobutanepropionic anhydride, cyclopentaneacetic anhydride,cyclohexaneacetic anhydride, cycloheptaneacetic anhydride,cyclohexanepropionic anhydride, etc.

The reaction between the anhydride and the desacetylcephalosporin ispreferably carried out in the presence of an organic base. Any of avariety of organic bases can be used for this purpose. Preferred organicbases are the secondary and tertiary amines having a pK less than 8.Representative of suitable bases are diethyl amine, triethyl amine,pyridine, piperidine, morpholine as well as a number of others known tothose skilled in the art.

If desired, the reaction can be carried out in the presence of an inertorganic solvent. However, since the organic base is generally a liquidunder normal conditions, it is usually preferred to operate without asolvent, using the organic base as the solvent.

The reaction temperature is not critical, and can be varied within wideranges. In general, use should be made of a reaction temperature withinthe range of --l0 to C., and preferably 0 to 30 C.

. The 7-acylamido group, and the residue of the ester forming alcohol (Rwhen use is made of a starting material in the form of an ester, do notenter into the reaction, and thus the nature of these groups does notaffect the nature of the reaction. For this reason, the 7-acylamidogroup and the R group (when the latter is other thanhydrogen) can be anyof a number of groups which are now well recognized by those skilled inthe penicillin and cephalosporin arts.

I Illustrative of suitable acyl groups which can be present in thestarting materials employed. in accordance i h h practice of theinvention include those acyl groups having the formula wherein n is zeroor an integer fnom I to 6 and R is an organic group such as HOOC-CH(NH)(CH or an aryl group or a substituted aryl group containing 6-14 carbonatoms.

Preferred aryl groups are those derived from benzene or naphthalene e MQ Q (XVII) gXVIII) wherein Q is hydrogen or one or more substituentsineluding, for example, C to C alkyl (e.g., methyl, ethylpropyl,isopropyl), C to C alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), acyano group, a nitro group, a hydroxy group, halogen (e.g., chlorine,fluorine, bromine and iod ne), a trifluoromethyl group, a carboxy group,an annno group, a C to C carboxyalkyl group (e.g., carboxyrnethyl,carboxyethyl, carboxypropyl, etc.), or a C to C4, carboxamidoalkyl group[H NC(0)-alkyl] (e.g., carboxamidomethyl, carboxamidoethyl, etc.).

Representative acyl groups are 5 aminoadipoyl, benzoyl, phenylacetyl,beta-(phenyl)propionyl, naphthoyl, naphthylacetyl, gamma-phenyl-butyryl,p-methylbenzooyl, 2,4 dimethylphenylacetyl, S-methoxynaphthylacetyl,p-cyanophenylacetyl, 4-nitronaphthoyl, 3-nitrobenzoyl, 3, 5dicyanonaphthylacetyl, beta-(3-nitrophenyl)-propionyl, p-hydroxybenzoyl,4-hydroxyphenylacetyl, p-chlorophenylacetyl, m-bromobenzoyl,3-trifluoromethylphenylacetyl,

o-carboxyphenylacetyl, m-carboxymethylphenylacetyl,mcarboxamidomethylphenylacetyl, beta(carboxamidomethylnaphthyl)propionyl, aminobenzoyl, aminophenylacetyl aswell as a number of others.

R can also be a cycloalkyl group containing 4-8 carbon atoms, includingcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In addition, R,can also be one of the foregoing cycloalkyl groups which is substitutedby one or more of the Q substituents described above.

Illustrative of such acyl groups include cyclopentanoyl, cyclohexanoyl,3 methylcyclohexanoyl, cyclobutylcarbonyl, 2 methoxycyclohexanoyl,3-chlorocyclohexylacetyl, cyclopentylacetyl, beta-cyclopentylpropionyl,3- methoxycyclohexylacetyl, 2-cyanocyclopentylacetyl,3-nitrocyclohexanoyl, 3 carboxycyclohexylacetyl,3-carboxamidomethylcyclohexylacetyl, etc.

R can also be a heterocyclic group wherein the heteroatom is O, S, N orany combination thereof, including dioxanyl, 2 furyl, 3-furyl,imidazolyl, isoxazolyl, morphorinyl, oxazolyl, pyranyl, pyrazinyl,pyrazolyl, N- pyridyl, 2 pyridyl, I l-pyridyl, pyridimidyl, N-pyrryl, 2-pyrryl, 3-pyrryl, thiazolyl, 2-thienyl, 3-thienyl, 2-benzothienyl,3-benzothienyl, triazinyl, triazolyl and the like;

the partially and completely hydrogenated derivatives of I theforegoing, such as tetrahydrofuryl, imidazolinyl, imidazolidyl,piperidyl, tetrahydropyrimidyl, pyrrolidyl and the like; as well as allof the foregoing group which are substituted by one or more of the Qgroups described above, as represented by the picolyls, methylfuryls,methyl thienyls, nitrofuryl, cyanofuryl, nitrobenzothienyl,nitropyridyl, cyanopyridyl, methoxypyrimidyl, bromopyridyl,trifiuoromethylpyridyl as well as others of the type described in FlynnUS. Pat. No. 3,218,318.

Illustrative of acyl groups when R is heterocyclic are dioxanylacetyl,2-fury1carbonyl, beta-pyrazinylpropionyl, 2 pyridylacetyl,3-pyridylcarbonyl, 2-thienylacetyl, 3- benzothienylcarbonyl,piperidylacetyl, pyrrolidylcarbonyl, nitrobenzothienylacetyl,beta-(nitrofuryl)-propionyl, cyanopyridylcarbonyl, etc.

The acyl group forming the 7-acylamido group can further be an acylgroup having the general formula R -i (XIX) wherein R is either alkylcontaining 1-8 carbon atoms (e.g., methyl, .ethyl, isopropyl, n-butyl,tert-butyl, hexyl, isooctyl, etc.) or alkenyl containing 28 carbon atoms(e.g., vinyl, allyl, Z-butenyl, 3-hexenyl, etc.). R; can also be one ofthe foregoing alkyl or alkenyl groups which is substituted by one ormore substituents including, for example, an amino group, a cyano group,a nitro group, a

hydroxy group, halogen (e.g., chlorine, fluorine, bromine,

iodine), a carboxy group or a carboxamide group Illustrative of theseacyl groups are acetyl, propionyl, acrylyl, crotoyl, 2 aminoacetyl,3-chloropropionyl, 6- heptenoyl, adipoyl, 3-hydroxypyropionoyl andS-nitrohexanoyl.

Also included within the scope of the invention are thosedesacetylcephalosporin compounds wherein R is an acyl group having theformula R5(CH2)m'-X(CH2)n -C (XX) wherein n is as previously described,m is zero or an integer from 1 to 5, X is O or S and R is R (i.e., aryl,cycloalkyl or heterocyclic) as described above including substitutedderivatives thereof, or R (i.e., C to C alkyl or C to C alkenyl) asdescribed above, including substituted derivatives thereof.

Representative of the acyl groups defined by (XX) above includetert-butoxycarbonyl, tert-butoxyacetyl, ethoxyacetyl,tert-butylmercaptocarbonyl, tert-butylmercaptoacetyl,allylmercaptoacetyl, 3 bromopropoxyacetyl,

3 hydroxypropylcarbonyl, Z-thienyloxyacetyl, piperidylmercaptoacetyl, 2pyridyloxycarbonyl, phenoxyacetyl, naphthoxyacetyl, phenoxycarbonyl,aminophenoxyacetyl, beta-(phenoXy)-propionyl, cyclohexyloxyacetyl,chlorocyclopentyloxyacetyl, benzylacetyl, phenylmercaptoacetyl,phenylbutoxyacetyl, phenylethylmercaptopropionyl andphenylmercaptoacetyl as well as a wide variety of others.

The 7-acyl group can further be an acyl group having the general formulaY (XXI) wherein Y is an amino group, a protected amino group, hydroxy, Cto C alkoxy (e.g., methoxy, ethoxy, etc.) carboxyl or C to C alkanoyloxy(e.g., acetoxy, propionoxy, etc.) and R isone of the groups defined by Rabove (i.e., aryl, heterocyclic and cycloalkyl as described in detailabove).

Representative of the foregoing acyl groups are 2-phenyl 2-aminoacetyl,2-(p-methoXyphenyl-2-aminoacetyl, 2- cyc1ohexyl-2-methoxyacetyl,2-phenyl-Z-acetoxyacetyl, 2- *(2' pyridyl)-2-hydroxyacetyl,2-piperidyl-2-aminoacetyl, 2 (2'-thienyl)-2-acetoxyacetyl as well as avariety of others. I

In addition to the foregoing, R can be a number of other acyl groups,including, for example, phenyl-a,a-di methylacetyl and Q substitutedderivatives thereof and a number of others. Various other suitable Racyl groups are disclosed in the Behrens et al. US. Pats. Nos. 2,479;295, 2,479,297, 2,562,407 and 2,623,876.

As will be appreciated by those skilled in the art, when the 7 acylamidogroup contains an unprotected amino group, such amino group may beacylated by the anhydride employed. However, this is not disadvantageoussince the 7-acylamido group can easily be removed to form thecorresponding 7-amino compound and reacylated as desired.

As indicated above, when use is made of an ester starting material, thenature of the reaction is not significantly affected by the nature ofthe ester protecting group or residue R It is generally preferred thatR; be an ester residue which is easily cleaved by known means, such asby dilute aqueous base, trifiuoroacetic acid or by hydrogenation in thepresence of a palladium or rhodium catalyst on a suitable carrier suchas carbon, barium sulfate or alumina so that the cephalosporin is notdegraded, since the ultimate product is generally used in the form ofthe acid.

Representative R groups include 0., to C tertiary alkyl (e.g.,tert-butyl, tcrt-pentyl, etc.), C to C tertiary alkenyl (e.g.,tert-pentenyl, tert-hexenyl, etc.), C to C tertiary alkynyl (e.g.,1,1-dimethyl-2-pentynyl, etc.), benzyl, methoxybenzyl, phenyl,methoxyphenyl, nitrobenzyl, phenacyl, trichloroethyl, trimethylsilyl,benzhydryl, phthalirnidomethyl, succinimidomethyl as well as a number ofothers apparent to those skilled in the art.

Examples of the A -desacetylcephalosporin acids and esters which can beused as the starting material in the practice of this invention includethe following.

7- (5 '-carb oxy-5 '-valeramido) 3-hydroxymethyl- A -cephem-4-carboxylicacid 7-phenoxyacetamido-3-hydroxymethyl-A -cephem- 4carboxylic acid7-phenylacetamido-3-hydroxymethyl-A -cephem- 4-carboxylic acidB,B,B-trichloroethyl 7-phenylmercaptoacetamido- 3-hydroxymethyl-Acephem-4-carboxylate 7-benzyloxyacetamido-3-hydroxymethyl-A -cephem-4-carboxylic acid tert-butyl 7-(4'-methylphenylbutyrylamido)-3-hydroxymethyl-A -cephem-4-carboxylate 7- (4-propylbenzylmercaptoacetamido) -3 -hydroxymethyl-A cephem-4-carboxylic acid1,1-dimethyl-2-pentynyl 7-(4-propylbenzy1-mercaptoacetamido)-3-hydroxymethyl-A -cephem-4-carboxylate7-benzylmercaptopropionamido-3-hydroxymethy1- A -cephemi-carboxylic acid7-phenylpr0pionarnido-3-hydroxymethyLM-cephem- 4-carb0xylic acidtert-butyl 7-phenylethylmercaptopropionamido-3- hydroxymethyl-A-cephem-4-carboxylate7-phenylethylmercaptopropionamido-3-hydr0xymethyl-A -cephem-4-carboxylicacid tert-butyl 7-phenylbutoxybutyrylamido-3-hydroxymethy1-A-cephem-4-carboxylic acid 7-pheny1butoxybutyrylamido-3-hydroxymethyl-Acephem-4-carboxy1ic acid benzyl7-phenylbutoxybutyrylamido-3-hydroxymethyl-A -cephem-4-carboxylate7-(3'-fiuorophenoxyacetamido)-3-hydroxymethy1- A -cephemi-carboxylicacid trimethylsilyl 7-(4-br0mopheny]acetamido)-3-hydroxymethyLM-cephem-4-carboxylate7-phenyl-a,a-dimethylacetamido-3-hydroxymethyl- A cephem-4-carboxylicacid p-nitrobenzyl 7-phenyl-a,a-dimethylacetamido-3-hydroxymethy1-A'--cephem-4-carb0xylate p-methoxybenzyl7-(2'-ch1orobenzyloxypropionamido)- 3-hydroXymethy1-A-cephem-4-carboxylate tert-butyl 7-benzamido-3-hydroxymethy1-A -cephem-4-carboxylate p-nitrobenzyl 7-phenylacetamido-3-hydroxymethyl- A-cepheIn-4-carb0xylate7-(4'-nitrophenylmercaptoacetamido)-3-hydroxymethy1-A-cephem-4-carboxylic acid 7- 3 '-cyanophenylpropionami do)-3-hydroxymethy1- A cephem-4-carboxylic acid 7- (3-trifluoromethylphenoxyacetamido -3 -hydroxymethyl-A-cephem-4-carboxylic acid 7-butyrylarnido-3-hydroxymethy1-A -cephem-4-carboylic acid tert-butyl 7-cyclohexylacetamido-3-hydroxymethyl- A-cephem-4-carboxylate 7-cyclohexy1acetamido-3-hydroxymethyl-A -cephem-4-carboxy1ic acid succinimidomethyl 7-(beta-aminopropionamido)-3-hydroxymethyl-A -cephem-4-carboxylate7-al1y1mercaptoacetamido-B-hydroxymethyl-A cephem-4-carboxylic acidp-methoxybenzyl 7-allylmercaptoacetamido-3- hydroxymethyl-A-cephem-4-carboxy1ate7-(gamma-chlorocrotyhnercaptoacetamido)-3-hydroxymethyl-A-cephemkcarboxylic acid tert-butyl 7-(5'-amin0-5-carboxyvaleramido)-3-hydroxymethyl-A -cephem-4-carboxylate7-(5'-amino-5'-carboxyvaleramido)-3-hydroxymethyl- A cephem-4-carboxylicacid 7-(2-thienylacetamido)-3-hydroxymethyl-A=-cephem- 4-carboxylic acidB,B,B-trich1oroethyl 7-(2-thienylacetamido)-3- hydroxymethyl-A-cephemi-carboxylate 7-(n-butylmercaptoacetamido)-3-hydroxymethy1-Acephem-4-carboxylic acid p-nitrobenzyl7-(tert-but0xyacetamido)-3-hydroxy methyl-A -cephem-4-carb0xylate7-tert-butoxyacetamido)-3-hydroxymethy1-A -cephem- 4-carboxylic acidbenzyl 7-(2'-benzothienylacetamido)-3-hydroxymethyl-A-cephem-4-carboxylate 7- (3 -pyridylacetamido) -3 -hydroxymethy1A-cephen-4- carboxylic acid 7-(2'-pyranylacetamido)-3-hydroxymethyl-A-cephemicarboxylic acid 7- ('5 '-ox azolylacetamido -3 -hydroxymethyl-A-cephem- 4-carboxylic acid tert-butyl7-(5-oxazolylacetamido)-3-hydroxymethyl- A -cephem-4-carboxylate Thestarting materials used in accordance with the process of this inventioncan be prepared by a number with citrus esterase to formdesacetylcephalosporin C which can then be esterified and isomerized asillustrated below:

i C 0 0H l Citrus esterase (B0011 (XXII) I Esterification 0 (U: sROOC-(IJH-(CHz)a- NH f 1 O-:IN -CHz-0H coon (XXIII) l Isomerization A OO R (XXIV) wherein R is the residue of the ester.

The product (XXIV) can then be reacted in accordance with the process ofthis invention.

Alternatively, the A -desacetylcephalosporin starting material can beprepared by simultaneous hydrolysis and isomerization of thecorresponding A -cephalosporanic acid derivative using the procedure ofCocker et al., J. Chem, Soc., sect. C, 1142 (1966)..

For example, cephalothin prepared in accordance with the procedure ofFlynn in the aforementioned U.S. patent can be hydrolyzed and isomerizedto the corresponding A -desacetylcephalosporin as follows NaOH . I o SCHr-i INHI( H O 'N CCH2OH xxxv The oxidation reaction of (XXVI) abovecan be carried out by, for example, the procedure described in copendingapplication Ser. No. 764,939, filed Oct. 3', 1968, wherein descriptionis made of the use of oxidizing agents such as per-acids (e.g.,peracetic acid, metachloroperbenzoic acid, etc.) for oxidizing A -cephemcompounds to the corresponding A -cephem sulfoxides;

Similarly, the reduction reaction of (XXVII) above can be carried out bythe use of any of a number of reducing agents, such as stannouschloride, zinc chloride or sodium dithionite, in conjunction with anacid halide activator (e.g., acetyl chloride) as described in copendingapplication Ser. No. 764,925, filed Oct. 3, 1968.

'It is intended that the 7-acylarnido group of the products of theprocess of the present invention may be removed and replaced by another7-acylamido group in the preparation of cephalosporin-type antibiotics.For example, the 7-acylamido group can be cleaved in accordance with theprocedure described by Chauvette in copending application, Ser. No.651,662, filed July 7, 1967, to form the corresponding 7-amino compoundwhich can, in turn, be

12 re-acylated with, for example, a heterocyclic-containing acylatingagent to prepare'the novel compounds of this invention as outlined belowo (f I COOR4 (LOORt I I" ii CH2C-Ol acylation JOOR Having described thebasic concepts of the invention, reference is now made to the followingexamples, which are provided by way of illustration, but not by way oflimitation, of the practice of the invention.

EXAMPLE 1 Preparation of 7 (2' thienylacetamido) 3cyclobutylcarbonyloxymethyl A cephem 4 carboxylic acid To a solution of2.12 g. (mM.) of 7-(2'-thienylacetamido)-3-hydroxymethyl-A-cephem-4-carboxylic acid 81 ml. (1 m.) of pyridine, 18 mM. ofcyclobutane carboxylic anhydride are added. The mixture is then stirredfor 40 minutes at room temperature, andthe solution is then poured .into500 ml. of cool 2 N HCl and cooled by stirring. The pH is 1.0.

The mixture is then extracted twice with ethyl acetate and thecephalosporin acid extracted with a solution of sodium bicarbonate untilthe pH is 7.7. The resulting alkaline solution is acidified to a pH of2.0 and extracted with ethyl acetate, the extract is washed with waterand dried. The product is identified as 7-(2-thienylacetamido)-3-cyclobutylcarbonyloxymethyl A cephem-4-carboxylic acid.

EXAMPLE 2 Preparation of 7 (2 thienylacetamido) 3cyclobutylcarbonyloxymethyl A cephem 1 oxide 4 carboxylic acid To asolution containing 1 mM. of 7'-(2-thienylacetarnido) 3cyelobutylcarbonyloxymethyl-M-cephem- 4-carboxylic acid, prepared inExample 1, 15 ml. of CHCl 190 mg. (0.95 mM.) of 85% monochloroperbenzoicacid are added. The mixture is warmed slightly and precipitationcommences. After stirring at room temperature for about 10 minutes,two-thirds of the solvent is evaporated and the product crystallized andfiltered and recrystallized from alcohol.

The product is identified as 7-(2-thienylacetamido)-3-cyclobutylcarbonyloxymethyl A cephem-l-oxide-4- carboxylic acid.

EXAMPLE 3 Preparation of 7 (2. thienylacetamido) 3cyclobutylcarbonyl-oxyrnethyl A cephem 4 carboxylic acid 1 mM. of the7-(2'-thienylacetamido)-3-cyclobutylcarbony1oxymethyl-A-cephem-1-oxide-4-carboxylic acid pre- 13 pared in Example 2, isdissolved in 18 ml. of dimethyl formamide and 560 mg. (2.5 mM.) ofstannous chloride dihydrate and 2.5 ml. of acetyl chloride are added.The mixture is stirred at 18 C. for 15. minutes, poured into 40 ml. ofcold water, and extracted 3 times with 25 ml. of

ethyl acetate. The combined extract is then washed with water and dried.The solvent is evaporated and the remaining oil dried in vacuo to yielda product having a melting point of 120122 C. dec.

. The product is identified as 7-(2'-thienylacetamido)-3-cyclobutylearbonyloxymethyl A cephem-4-carboxylic acid.

EXAMPLE 4 Preparation of 7 (2' furylpropionamido) 3cyclohexylcarbonyloxymethyl A cephem 4 carboxylic acid 7 (2'furylpropionamido) 3 hydroxymethyl A cephem-4-carboxylic acid isprepared by hydrolysis of 7-(2'-furylpropionamido)cephalosporanic acidprepared in accordance with Example 2 of US. Pat. No. 3,218,318.

The resulting 3-hydroxymethyl compound is reacted with cyclohexanecarboxylic anhydride according to the procedure of Example 1 to form7-(2'-furylpropionamido)-3- cyclohexylcarbonyloxymethyl Acephem-4-carboxylic acid.

The A -compound is then oxidized with metachloroperbenzoic acid to formthe corresponding sulfoxide and then reduced with sodium dithionite inaknown manner. The product is identified as 7-(2-furylpropionamido)-3-cyclohexylcarbonyloxymethyl-A -cephem 4 carboxylic acid.

EXAMPLE 5 Preparation of7-(2-furylacetamido)-3-cyclopentylcarbonyloxymethyl-A-cephem-4-carboxylic acid 7-(2-furylacetamido) 3 hydroxymethyl-A-cephem- 4-carboxylic acid prepared by hydrolysis of the Acephalosporanic acid is reacted with cyclopentanecarboxylic anhydride inaccordance with the procedure of Example 1. The product is identified as7-(2'-furylacetamido)-3- cyclohexylacetoxymethyl-A -cephem-4-carboxylicacid The resulting A -compound is then oxidized with metachlorperbenzoicacid and reduced with stannous chloride to form7-(2-furylacetamido)-3-cyclopentylcarbonyloxymethyl-A-cephem-4-carboxylic acid.

EXAMPLE 6 Preparation of 7-(N'-methyl 2 pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem-4-canboxylic acid 7-(N-methyl 2pyrrylacetamido)cephalosporanic acid prepared in accordance with themethod described in Example 14 of US. Pat. No. 3,218,318 is hydrolyzedto form the corresponding A -desacetylcephalosporanic acid. Theresulting product is 7-(N'-methyl-2-pyrrylacetamido)-3-hydroxymethyl-A-cephem 4 carboxylic acid which is reacted with cyclohexylaceticanhydride in accordance with the procedure described in Example 1.

The resulting product is7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem 4carboxylic acid which is oxidized and then reduced in accordance withthe methods of Examples 2 and 3, respectively, to form7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A-cephem4-carboxylic acid.

EXAMPLE 7 Preparation of 7-(2'-4-dimethylthiazol- -acetamido)-3-cyclopentylearbonyloxymethyl-A -cephem 4 carboxylic acid7-(2-4'-dimethylthiazol 5' acetamido)cephalosporanic acid prepared inaccordance with the procedure in Example 13 of US. Pat. No. 3,218,318 ishydrolyzed in 14 accordance with the procedure described in Example 6 toform 7-(2-4'-dimethylthiazol-5-acetamido) 3 hydroxymethyl-A-cephem-4-carboxylic acid.

This product is then reacted with cyclopentanecarboxylic anhydride inaccordance with the procedure of Example 1 to form tertiary butyl7-(2'-4-dimethylthiazol- 5'-acetamido)-3-cyclopentylcarbonyloxymethyl A-cephem-4-carboxylate.

This product is then oxidized and reduced in accordance with theprocedure of Example 6 to form the corresponding7-(2'-4'-dimethylthiazol-5-acetamido)-3-cyclopentylcarbonyloxymethyl-A-cephem-4-carboxylic acid.

EXAMPLE 8 Preparation of 7-(1'--4-triazol-.l'-acetamido)-3-cyclobutylacetoxymethyl-A-cephem-4-carboxylic acid Using the procedure described in Example 7, 7(1'-2- '-triazol-l-acetamido)cephalosporanic acid prepared in accordancewith the US. Pat. No. 3,218,318, is hydrolyzed to form the correspondingA -desacetyl compound which is reacted with cyclobutylacetic anhydridein accordance with the procedure described in Example 1.

The resulting product is then oxidized and reduced to form 7 (12-4'-triazol-1-acetamido)-3-cyclobutylacetoxymethyl-A-cephem-4-carboxylic acid.

EXAMPLE 9 Preparation of7-(1'-pyrazoleacetamido)-3-cyclohexylcarbonyloxymethyl-M-cephem-4-carboxylicacid 7 (1 pyrazolacetamido)cephalosporanic acid is hydrolyzed inaccordance with the procedure described in Example 6 to form thecorresponding A desacetylcephalosporanic compound, which is then reactedwith cyclohexane carboxylic anhydride in accordance With the proceduredescribed in Example 1.

The product is then oxidized and reduced to convert the A -compound tothe A -compound, and the resulting product is identified as7-(1-pyrazolacetamido)-3-cyclohexylcarbonyloxymethyl-A-cephem-4-carboxylic acid.

EXAMPLE 10 Preparation of 7-(3-thienylacetamido) 3 cyclopentylprop1onoxymethyl-A -cephem-4-carboxylic acid potassium salt7-(3-thienylacetamido 3 hydroxymethyl-A -cephem- 4-carboxylic acidprepared by hydrolysis of 7-(3'-thienylacetamido) cephalosporanic acidprepared in accordance with Example 5 of US. Pat. 3,218,318, is reactedwith cyclopentanepropionic anhydride in accordance with the proceduredescribed in Example 1.

The resulting product is then oxidized and reduced in accordance withthe procedure described in Examples 2 and 3, respectively, to yield7-(3-thienylacetamido)-3-cyclopentylpropionoxymethyl A-cephem-4-carboxylic acid, which is, in turn, reacted with potassiumacetate to form the corresponding potassium salt.

EXAMPLE 11 Preparation of 7-(2-thienylacetamido)-3-propionoxymethyl-A-cephem-4-carboxylic acid To a solution of 2.12 g. (6 mM.) of7-(2-thienylacetamido)-3-hydroxymethyl-A -cephem-4-carboxylic acid in 81ml. (1 mole) of pyridine, 2.34 g. (18 mM.) of propionic anhydride areadded. The mixture is then stirred 40 minutes at room temperature.Thereafter, the solution is poured into 500 ml. of cold 2 N HCl andcooled by stirring; the pH is 1.0.

The mixture is then extracted twice with ethyl acetate, and the acidextracted with a solution of sodium bicarbonate until the pH is 7.7. Thealkaline solution is acidified to a pH of 2.0 and extracted with ethylacetate, the extract being washed with water and dried. The solvent isextracted and the remaining oil triturated with petroleum ether givingthe powdered product (1.1 g.', 44.5%) MP. 1l0-113 dec.

The product is identified as 7-(2'-thienylacetamido)-3-propionoxymethyl-A -cephem-4-carboxylic acid.

Analysis.--Calcd. for c qH gNgossz (percent): 49.74; H, 4.42; N, 6.82;S, 15.64. Found (percent): C, 49.61; H, 4.40; N, 6.63; S, 15.57.

EXAMPLE 12 Preparation of 7-(2'-thienylacetamido) -3-butyryloxymethyl-A-cephem-4-carboxylic acid Using the procedure described in Example 11,butyric anhydride is reacted with 7 (2' thienylacetamido)-3-hydroxymethyl A cephem 4 carboxylic acid. After separation of thereactants from the reaction mixture, the product is identified as 7-(2'thienylacetamido)-3-butyryloxymethyl-A -cephem-4-carboxylic acid.

EXAMPLE 13 Preparation of 7-(2-thienylacetamido)-3-isobutyryloxymethyl-A-cephem-4-carboxylic acid Using the procedure described in Example 1,isobutyric anhydride is reacted with7-(2'-thienylacetamido)-3-hydroxymethyl A cephem 4 carboxylic acid.After separation of the reactants from the reaction mixture, the productis identified as 7-(2'-thienylacetamid0) 3 isobutyryloxymethyl-A-cephem-4-carboxylic acid.

EXAMPLE 14 Preparation of7-phenoxyacetamido-3-propionoxymethyl-M-cephem-l-carboxylic acid 7phenoxyacetamido 3 hydroxymethyl-A -cephem- I-carboxylic acid is reactedwith propionic anhydride in accordance with the procedures of Example 1.The resulting product is identified as 7-phenoxyacetamido-3-propionoxymethyl-A -cephem-l-carboxylic acid.

EXAMPLE 15 Preparation of7-benzylmercaptoacetamido-3-is0butyrylxymethyl-A -cephem-4-carboxylicacid 7 benzylmercaptoacetamido 3 hydroxymethyl-M- cephem-4-carboxylicacid is reacted with iso'butyric anhydride in accordance with theprocedures of Example 1. The product is identified as7-benzylmercaptoacetamido- 3-isobutyryloxymethyl-A -cephem-4-carboxylicacid.

EXAMPLES 16-23 Using the procedure described in Example 1, the following3-acyloXymethylA -compounds are prepared from the reactants asindicated.

7-phenylacetyl 3 acetoxymethyl A cephem-4-carboxylic acid from aceticanhydride and 7-phenylacetyl- 3-hydroxymethyl-A -cephem-4-carboxylicacid 7-phenylmercaptoacetamido 3 propionoxymethyl-M- cephem 4 carboxylicacid from propionic anhydride and 7-phenylmercaptoacetamido 3hydroxymethyl- A -cephem4-carboxylic acid 7-(3'-benzylmercaptoacetamido)3 butyryloxymethyl- A -cephem 4 carboxylic acid from butyric anhydrideand 7-(3' benzylmercaptoacetamido) 3 hydroxyrnethyl-A cephem-4-carboxy1ic acid 7 cyclohexylacetamido 3 propionoxymethyl A cephem 4carboxylic acid from propionic anhydride and 7-cyclohexylacetamido 3hydroxymethyl- A -cephem-4-carboxylic acid 7 allylmercaptoacetamido 3cyclopentylcarbonyloxymethyl A cephem 4 carboxylic acid fromcyclopentane carboxylic anhydride and 7 allylmercaptoacetamido 3hydroxymethyl A cephem-4-carboxylic acid B,B,B-trichloroethyl 7-(5carboxy propionamidovaleramido) 3 propionoxymethyl 2 cephem 4-carboxylate from propionic anhydride and B,B,B-tri- It will beunderstood that various changes and modifications can be made in thedetails of procedure, formulation and use without departing from thespirit of the invention, especially as defined in the following claims.

I claim:

1. A process for preparing a 3-acyloxymethyl-A cephalosporin comprisingreacting a 7-acylamido-3-hydroxymethyl-A -cephalosporin having theformula wherein R is the residue of the 7-acylamido group and R isselected from the group consisting of hydrogen and the residue of anester forming alcohol which can be cleaved by dilute aqueous base, bytrifluoroacetic acid or by hydrogenation in the presence of a palladiumor rhodium catalyst on a carrier, with the anhydride of a saturatedaliphatic carboxylic acid in which the anhydride contains 4 to 20 carbonatoms in the presence of an organic base having a pK less than 8.

2. A process as defined in claim 1 wherein the anhydride is an anhydridehaving the formula wherein R is selected from the group consisting of Cto 0; alkyl and cycloalkyl having the structure Ii JEEP-(0112)::-

wherein n is zero or an integer from 1 to 5 and R is alkylene containing1-5 carbon atoms.

3. A process as defined in claim 1 wherein the organic base is pyridine.I

4. A process as defined in claim 1 wherein R is selected from the groupconsisting of hydrogen, C; to C tertiary alkyl, C to C tertiary alkenyl,C to C tertiary alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl,trichloroethyl trimethylsilyl, benzhydryl, phthalimidomethyl, phenyl,methoxyphenyl and succinimidomethyl.

5. A process as defined in claim 1 wherein the acyl group in the7-position is an acyl group selected from the group consisting of (1) anacyl group having the formula wherein n is zero or an integer from 1 to6 and R is selected from the group consisting of monocyclic carbocyclicand bicyclic carbocylic aryl containing 6-14 carbon atoms cycloalkylcontaining 48 carbon atoms and heterocyclic groups wherein the heteroatom is selected from the group consisting of O, S, N and combinationsthereof, and substituted derivatives thereof wherein the substituent isselected from the group consisting of C C alkyl, C -C alkoxy, cyano,nitro, hydroxy, halogen, trifluoromethyl,

17 carboxy, amino, C -C carboxy alkyl and C C carboxamido alkyl; (2) anacyl group having the formula l R7-C wherein R is selected from thegroup consisting of C to C alkyl, C to C alkenyl and substitutedderivatives thereof wherein the substituent is selected from the groupconsisting of amino, cyano, nitro, hydroxy, halogen, carboxy andcarboxamido; (3) an acyl group having the formula i Ra-(CHz)mX(ClIz)n-Gwherein n has the meaning set forth above, In is zero or an integer from1 to 5, X is O or S and R is selected from the group consisting of R Cto C alkenyl and substituted C to C alkenyl derivatives wherein thesubstituent is selected from the group consisting of amino, cyano,nitro, hydroxy, halogen, carboxy and carboxamido; (4) an acyl grouphaving the formula wherein R has the meaning defined above and Y isselected from the group consisting of amino, protected amino, hydroxy, Cto C alkoxy, carboxyl, and C to C alkanoyloxy; andphenyl-a,a-dimethylacetyl and substituted derivatives thereof whereinthe substituent is selected from the group consisting of C -C alkyl, C-C alkoxy, cyano, nitro, hydroxy, halogen, trifluorornethyl, carboxy,amino, C -C carboxy alkyl and (D -C carboxamido alkyl.

6. A process as defined in claim 1 wherein the reaction is carried outat a temperature within the range of 10 to 100 C.

7. A compound of the formula wherein R is a heterocyclic group selectedfrom the group consisting of dioxanyl, furyl, imidazolyl, isoxazoly],morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl,pyrimidyl, pyrryl, thiazolyl, thienyl, benzothienyl, triazinyl,triazolyl, tetrahydrofuryl, imazolinyl, imidazolidy], piperidyl,tetrahydropyrimidyl, pyrrolidyl, and heterocyclic groups as set forthabove which are substituted by one or more of the groups selected fromthe group consisting of C to C alkyl, C to C alkoxy, a cyano group, anitro group, a hydroxy group, halogen, a trifluoromethyl group, acarboxy group, an amino group, a C to C carboxyalkyl group and a C to Ccarboxamidoalkyl group; n is Zero or an integer from 1 to 5; and R is Cto C alkylene and m is zero or an integer from 1 to 3, andpharmaceutically acceptable cationic salts thereof.

8. A- compound of the formula wherein R is C to C alkylene and m is zeroor an integer from 1 to 3, and pharmaceutically acceptable cationicsalts thereof.

9. 7 (2' thienylacetamido) 3 cyclobutylcarbonyloXymethyl-A-cephem-4-carboxylic acid.

References Cited UNITED STATES PATENTS 3,532,694 10/1970 Somerfield260-243 C NICHOLAS S. RIZZO, Primary Examiner U.S. Cl. X.R. 424246

